Stigma Research Funded by National Institute of Mental Health (NIMH) NIMH Grant # 1 R24 MH068180-04.
Perspectives from the NIMH - aadcap.org Presentations/Gordon_JAG_042519.pdf · Psychiatric...
Transcript of Perspectives from the NIMH - aadcap.org Presentations/Gordon_JAG_042519.pdf · Psychiatric...
Perspectives from the NIMH
Joshua A. Gordon, M.D., Ph.D.
Director
National Institute of Mental HealthApril 26, 2019
Follow me on twitter @NIMHDirector
• NIMH and the Neurodevelopmental Perspective
• Autism: Harnessing Genetics & Developmental Neuroscience
• Approaches to Early Intervention
■ Autism
■ Schizophrenia
• Platforms for Understanding Risk & Resilience Pathways in Development
• Discussion
Agenda
2
• NIMH and the Neurodevelopmental Perspective
• Autism: Harnessing Genetics & Developmental Neuroscience
• Approaches to Early Intervention
■ Autism
■ Schizophrenia
• Platforms for Understanding Risk & Resilience Pathways in Development
• Discussion
Agenda
3
About the NIMH
• The National Institute of Mental Health (NIMH) is the lead federal agency for research on mental illnesses.
• NIMH supports more than 3,000 research grants and contracts at universities and other institutions across the country and overseas.
• NIMH intramural research programs support approximately 600 scientists working on the NIH campuses.
(Neuro)developmental Perspective
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Early & Differential Onset
Roots in Neurodevelopment
Early insult alters trajectories
Early interventions improve outcomes
Psychiatric Disorders Onset During
Childhood and Adolescence
6 Casey et al. Biol Psychiatry, 2014
• NIMH and the Neurodevelopmental Perspective
• Autism: Harnessing Genetics & Developmental Neuroscience
• Approaches to Early Intervention
■ Autism
■ Schizophrenia
• Platforms for Understanding Risk & Resilience Pathways in Development
• Discussion
Agenda
7
Neurodevelopmental Pathway to Autism
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• Birth
• 4 years
• Prenatal
• 18-24 months
Brain Development
Genetic and
Environmental Risk
Joseph Tart/EHP; Clouchoux, Brain Structure and Function, 2012; NIH
Early Treatment
Improves
Outcomes
Screening
Exome analysis of 35,584 samples identified 99 ASD-associated
genes
Genetic Risk for ASD
9 Satterstrom … Daly, preprint, 2018
GWAS analysis of over 18,000 ASD cases identifies 2-5 loci from common variants
Grove, Nature Genetics, 2019
KMT2E,
SRPK2
MACROD2LOC1027
23661,
PTBP2
C8orf74,
SOX7KIZ,
XRN2
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Genetic Risk for ASD
Likely Complexity
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Towards Genome-Scale Neurobiology
Penetrant Risk
Loci
(KDM5b, NRXN1,
CNTNAP2, ARID1B,
dup15q, …)
CONVERGENCECONVERGENCE
human forebrain spheroids (hFS*)
CellularCellular MolecularMolecularAnatomic/
Structural
Anatomic/
StructuralPhysiologyPhysiology
• Composition
• Fate
• Migration
• Identity
• Maturity
• Regulatory
networks
• Dendritic spines
• Synaptic
connectivity
• Intrinsic properties
• Synaptic activity
• Network activity
sc-RNAseq / RNAseqimaging
slice recordings
Bottom
10% PGR
for ASD
Top 10%
PGR for ASD
Network
In Vivo Ephys
and Behavior
In Vivo Ephys
and Behavior
Adapted from Sergiu Pasca and John Hugenard12
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• Birth
• 4 years
• Prenatal
• 18-24 months
Brain Development
Genetic and
Environmental Risk
Joseph Tart/EHP
Early Treatment
Improves Outcomes
Screening
From risk factors
to mechanisms
Early identification
and early
intervention
Improved therapeutic
approaches
throughout the lifespan
Research Strategy
Neurodevelopmental Pathway to Autism
• NIMH and the Neurodevelopmental Perspective
• Autism: Harnessing Genetics & Developmental Neuroscience
• Approaches to Early Intervention
■ Autism
■ Schizophrenia
• Platforms for Understanding Risk & Resilience Pathways in Development
• Discussion
Agenda
14
Early Trajectories Predict ASD
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Hazlett, Nature, 2017
Brain Growth Predicts Autism Diagnosis
Children’s Early Visual Behavior Predicts Autism
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Constantino, Nature, 2017
Eye Gaze in Autism
Children’s Early Visual Behavior Predicts Autism
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Constantino, Nature, 2017
Eye Gaze in Autism
Early Interventions Improve Outcomes
18 Rogers, JAACAP, 2019; Kasari, J Consult Clin Psychol, 2016
• NIMH and the Neurodevelopmental Perspective
• Autism: Harnessing Genetics & Developmental Neuroscience
• Approaches to Early Intervention
■ Autism
■ Schizophrenia
• Platforms for Understanding Risk & Resilience Pathways in Development
• Discussion
Agenda
19
The Problem
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TreatmentEarlier?
Early/Personalized Intervention
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• Recovery After an Initial Schizophrenia Episode (RAISE) initiative
Client
Medication/ Primary Care
Psychotherapy
Family Education and
Support
Supported Employment
and Education
Case Management
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Kane, et al., Am. J. Psychiatry, 2016 22
Participants with shorter duration of untreated psychosis had greater
improvement in quality of life and psychopathology over 2 years
Early Intervention
TX
UT
MT
CA
AZ
ID
NV
OR
IA
CO
KS
WY
NM
MO
MN
NE
OK
SD
WA
AR
ND
LA
IL OH
FL
GAAL
WI
VA
IN
MI
MS
KY
TN
PA
NC
SC
WV
ME
NY
VT12
AK
Early Intervention Programs, 2008
August 2008 – 12 clinics
HI
CT
DE
MA
NH
NJ
RI
VT
TX
UT
MT
CA
AZ
ID
NV
OR
IA
CO
KS
WY
NM
MO
MN
NE
OK
SD
WA
AR
ND
LA
IL OH
FL
GAAL
WI
VA
IN
MI
MS
KY
TN
PA
NC
SC
WV
ME
NY
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37
1415
20
88 8
9
7
5
10
AK
Early Intervention Programs, 2018
August 2018 – 265 clinics
1-4
HI
5
The Problem
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Etiology Plasticity Treatment
?• Improve outcomes
• Alter progression
• “Recovery”
What’s New: Getting Earlier
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Genetics Risk Prediction
Parsing Heterogeneity
27Insel & Cuthbert, Science 2015
Patterns of Resting State Connectivity
Drysdale…Liston, Nature Medicine, 20172828
Clustering Patients Based on Connectivity
Drysdale…Liston, Nature Medicine, 20172929
Subtypes Differ in Responsivity to Prefrontal Cortex
Repetitive Transcranial Magnetic Stimulation
Drysdale…Liston, Nature Medicine, 20173030
• NIMH and the Neurodevelopmental Perspective
• Autism: Harnessing Genetics & Developmental Neuroscience
• Approaches to Early Intervention
■ Autism
■ Schizophrenia
• Platforms for Understanding Risk & Resilience Pathways in Development
• Discussion
Agenda
31
• Map the neural pathways that underlie human brain function
• Deciphering the brain’s complex wiring system
■ Mapping the connectomes in over 1,000 healthy adults
■ Optimizing MRI technology for imaging brain structure
Human Connectome Project (HCP)
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• Baby Connectome:
■ Ages 0-5 years; 500 participants; cross-sectional and longitudinal
• Development Connectome:
■ Ages 5-21 years; 1350 participants; cross-sectional and longitudinal
• Young Adult Connectome (initial HCP)
■ Ages 22-35; 1200 participants, twin pairs, siblings
• Aging Connectome:
■ Ages 36 – 100; 1200 participants
Lifespan Connectome
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Adolescent Brain Cognitive Development
(ABCD) Study
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• Multisite, longitudinal study of children from ages 9-10 through early adulthood
• Examines how childhood experiences (e.g., sports, videogames, social media, unhealth sleep patterns, etc.) affect brain, social, emotional, and cognitive development and other outcomes
Adolescent Brain Cognitive Development
(ABCD) Study
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• Almost 12,000 youth ages 9 -10 enrolled to date
• Baseline data now available through NIMH Data Archive data tool
■ Data Exploration and Analysis Portal for online analyses
■ Data analysis, statistical models, and tools available online
HEALthy Brain and Child Development
(HBCD) Study
Large multi-site longitudinal study to examine brain, cognitive, behavioral, social, and emotional development beginning prenatally and extending through childhood (9-10).
• Oversample for prenatal opioid exposure
• Fall 2018: Expert Panels
• R34 Planning Grant Announcements – RFA-DA-19-029; RFA-DA-19-036
oPublished – December 21, 2018
oApplication deadline – March 25, 2019
oReview – July 2019
oEarliest start date – September 2019
• NIMH and the Neurodevelopmental Perspective
• Autism: Harnessing Genetics & Developmental Neuroscience
• Approaches to Early Intervention
■ Autism
■ Schizophrenia
• Platforms for Understanding Risk & Resilience Pathways in Development
• Discussion
Agenda
37
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NIMH’s Mission
www.nimh.nih.gov
Research = Hope
Understanding ASD Risk: Genes + Environment
Gaugler, Nature Genetics, 2014
Searching for
Unaccounted Risks
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